WO2021153984A1 - 벤조셀레노펜계 화합물, 이를 포함하는 약학적 조성물 및 항체-약물 결합체 - Google Patents

벤조셀레노펜계 화합물, 이를 포함하는 약학적 조성물 및 항체-약물 결합체 Download PDF

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Publication number
WO2021153984A1
WO2021153984A1 PCT/KR2021/001082 KR2021001082W WO2021153984A1 WO 2021153984 A1 WO2021153984 A1 WO 2021153984A1 KR 2021001082 W KR2021001082 W KR 2021001082W WO 2021153984 A1 WO2021153984 A1 WO 2021153984A1
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group
cancer
antibody
compound
substituted
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PCT/KR2021/001082
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English (en)
French (fr)
Korean (ko)
Inventor
임동열
김민철
메트레아몰
남도현
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Aimed Bio Inc
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Aimed Bio Inc
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Priority to JP2022546665A priority Critical patent/JP7504209B2/ja
Priority to AU2021212559A priority patent/AU2021212559B2/en
Priority to CN202180012034.0A priority patent/CN115038699B/zh
Priority to CA3165524A priority patent/CA3165524C/en
Priority to EP21748317.1A priority patent/EP4083041A4/en
Publication of WO2021153984A1 publication Critical patent/WO2021153984A1/ko
Priority to US17/815,958 priority patent/US11938115B2/en
Anticipated expiration legal-status Critical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D421/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having selenium, tellurium, or halogen atoms as ring hetero atoms
    • C07D421/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having selenium, tellurium, or halogen atoms as ring hetero atoms containing two hetero rings
    • C07D421/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having selenium, tellurium, or halogen atoms as ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
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Definitions

  • the present application relates to a benzoselenophene compound, a method for preparing the benzoselenophene compound, a pharmaceutical composition comprising the benzoselenophene compound, and an antibody-drug conjugate.
  • Duocarmycin is known as a highly effective anticancer drug. However, in the course of animal experiments, duocarmycin also acts as a toxin to normal cells and kills experimental animals, so the substance itself could not be used in humans. Research is being actively conducted to maintain stability and high activity in the body.
  • Antibody therapy is being used for targeted treatment of patients with cancer, immunological disorders and angiogenic disorders.
  • ADC antibody-drug conjugate
  • drugs such as cytotoxic agents or cytostatic agents that kill or inhibit tumor cells in cancer treatment
  • the present application provides a benzoselenophene-based compound, a method for preparing the benzoselenophene-based compound, a pharmaceutical composition including the benzoselenophene-based compound, and an antibody-drug conjugate.
  • the present application relates to the preparation of a novel benzoselenophene derivative with greatly increased water solubility and activity by introducing a novel water-soluble group to benzoselenophene, and to using the benzoselenophene derivative as an anticancer agent.
  • the novel water-soluble benzoselenophene derivative of the present application can be applied as an antibody-drug conjugate and can function as a prodrug.
  • the water-soluble benzoselenophene derivative can be used by conjugating not only an antibody but also a target-directing substance such as a protein, a ligand, a nanoparticle, and an aptamer, which can function as a prodrug.
  • a first aspect of the present application provides a benzoselenophene-based compound, represented by the following Chemical Formula 1:
  • R 1 is a substituted or unsubstituted C 3-10 heterocycloalkyl group, a substituted or unsubstituted C 5-10 aryl group, or a substituted or unsubstituted C 3-10 heteroaryl group,
  • R 2 and R 3 are each independently hydrogen, fluorine, chlorine, bromine, iodine, or a substituted or unsubstituted C 1-5 alkyl group,
  • R 4 and R 5 are each independently hydrogen, or a substituted or unsubstituted C 1-5 alkyl group
  • the heterocycloalkyl group and the heteroaryl group include one or more heteroatoms selected from N, O, and S,
  • X is a halogen element
  • a second aspect of the present application is to prepare an intermediate product by (a) reacting a carboxylic acid represented by the following formula (2) with an amine represented by the following formula (3); (b) reacting the intermediate product with an amine represented by the following formula (4) to obtain a benzoselenophene-based compound represented by the following formula (1).
  • R 1 is a substituted or unsubstituted C 3-10 heterocycloalkyl group, a substituted or unsubstituted C 5-10 aryl group, or a substituted or unsubstituted C 3-10 heteroaryl group,
  • R 2 and R 3 are each independently hydrogen, fluorine, chlorine, bromine, iodine, or a substituted or unsubstituted C 1-5 alkyl group,
  • R 4 and R 5 are each independently hydrogen or a substituted or unsubstituted C 1-5 alkyl group
  • R 6 is a substituted or unsubstituted C 1-5 alkyl group
  • the heterocycloalkyl group and the heteroaryl group include one or more heteroatoms selected from N, O, and S,
  • X is a halogen element
  • a third aspect of the present application provides a pharmaceutical composition
  • a pharmaceutical composition comprising a benzoselenophen-based compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof, for preventing or treating a proliferative disease:
  • R 1 is a substituted or unsubstituted C 3-10 heterocycloalkyl group, a substituted or unsubstituted C 5-10 aryl group, or a substituted or unsubstituted C 3-10 heteroaryl group,
  • R 2 and R 3 are each independently hydrogen, fluorine, chlorine, bromine, iodine, or a substituted or unsubstituted C 1-5 alkyl group,
  • R 4 and R 5 are each independently hydrogen or a substituted or unsubstituted C 1-5 alkyl group
  • the heterocycloalkyl group and the heteroaryl group include one or more heteroatoms selected from N, O, and S,
  • X is a halogen element
  • a fourth aspect of the present application is an antibody; linker; And it provides an antibody-drug conjugate (antibody-drug conjugate) or a pharmaceutically acceptable salt thereof, comprising a benzoselenophen-based compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof:
  • R 1 is a substituted or unsubstituted C 3-10 heterocycloalkyl group, a substituted or unsubstituted C 5-10 aryl group, or a substituted or unsubstituted C 3-10 heteroaryl group,
  • R 2 and R 3 are each independently hydrogen, fluorine, chlorine, bromine, iodine, or a substituted or unsubstituted C 1-5 alkyl group,
  • R 4 and R 5 are each independently hydrogen or a substituted or unsubstituted C 1-5 alkyl group
  • the heterocycloalkyl group and the heteroaryl group include one or more heteroatoms selected from N, O, and S,
  • X is a halogen element
  • a fifth aspect of the present application provides an anticancer composition comprising the antibody-drug conjugate according to the fourth aspect or a pharmaceutically acceptable salt thereof.
  • a novel benzoselenophene derivative having greatly increased water solubility and activity by introducing a new water-soluble group can be prepared, and the benzoselenophene derivative can be used as an anticancer agent.
  • the novel water-soluble benzoselenophene derivative of the present application can be applied as an antibody-drug conjugate and can function as a prodrug.
  • the water-soluble benzoselenophene derivative can be used by conjugating not only an antibody but also a target-directing substance such as a protein, a ligand, a nanoparticle, and an aptamer, which can function as a prodrug.
  • the benzoselenophene-based compounds according to the embodiments of the present application are substances having a very strong anticancer effect with an IC 50 of nM or pM units for cancer cells, and can be utilized for new drug development using an antibody-drug conjugate.
  • the benzoselenophene-based compound according to the embodiments of the present application, a pharmaceutical composition comprising the same, and an antibody-drug conjugate have a remarkable therapeutic effect on cancer, in particular, in brain cancer, brain metastasis, non-small cell lung cancer, and melanoma. It has excellent anticancer and therapeutic effects.
  • a DNA alkylation derivative including a benzoselenophene-based compound having excellent water solubility and activity may be synthesized, and this may be used as an anticancer agent or a precursor thereof.
  • the benzoselenophene compound derivative according to the embodiments of the present application may be conjugated to an antibody-drug conjugate or a protein-conjugate to act in a target-directed manner on a target, thereby retaining a selective effect through specific treatment.
  • the benzoselenophen derivative (precursor, prodrug), benzoselenophen derivative-linker, benzoselenophen derivative-linker-ligand conjugate according to the embodiments of the present application is stable as such, but proliferative diseases such as cancer (especially , brain cancer, brain metastasis, melanoma, non-small cell lung cancer) has industrial utility in that it is possible to target, specific treatment, and/or maximize drug efficacy.
  • FIG. 2 shows the HIC analysis results of trastuzumab-Glucuronide-Compound 3 ADC prepared according to an embodiment of the present application.
  • FIG. 3 shows the PLRP analysis results of Trastuzumab-Glucuronide-Compound 3 ADC prepared according to an embodiment of the present application.
  • 5 is a graph relating to the in vivo cell line activity analysis of compound 3 (DS-24) prepared according to an embodiment of the present application.
  • Figure 7a is a graph showing the nonlinear regression analysis of the dose-response curve for cell viability for ADC (DS-24) of MCF-7 and NCI-N87 cells
  • Figure 7b is data showing the resulting IC 50 values. am.
  • FIG. 8A is a setting for confirming the BT474 tumor spheroid inhibitory efficacy of ADC (DS-24)
  • FIG. 8B is a graph showing a nonlinear regression analysis for a dose-response curve
  • FIG. 8C is a result IC 50 value data shown.
  • 9A and 9B are data on the anticancer efficacy of ADC (DS-24) in the NCI-N87 xenograft animal model and the change in body weight of the administered subject, nude mice, respectively.
  • 10A and 10B show inflammatory cell counts and anemia-related levels according to toxicity analysis according to whole blood cell analysis (CBC test) of ADC (DS-24) in the NCI-N87 xenograft animal model, respectively.
  • 11A, 11B and 11C are data confirming the cell viability inhibitory efficacy of compound 3 (DS-24) and 7 other payloads against the glioblastoma cell line U87MG, the multiple myeloma cell line KMS11, and the bladder cancer cell line RT112, respectively.
  • 12a, 12b, 12c, 12d, 12e, and 12f are data confirming the cell viability inhibitory effect of compound 3 (DS-24) and 7 types of payloads on 6 types of glioblastoma patient-derived cells, respectively am.
  • 13A and 13B are graphs showing cell viability according to the concentration of DS-24 and DS-26 for NCI-N87, respectively.
  • 14A and 14B are graphs showing the cell viability according to the concentration of DS-24 and DS-26 for SK-OV3, respectively.
  • step of doing or “step of” does not mean “step for”.
  • alkyl refers to a linear or branched alkyl group having 1 to 12 carbon atoms, 1 to 10 carbon atoms, 1 to 8 carbon atoms, or 1 to 5 carbon atoms. and all possible isomers thereof.
  • the alkyl or alkyl group is a methyl group (Me), an ethyl group (Et), an n-propyl group ( n Pr), an iso-propyl group ( i Pr), an n-butyl group ( n Bu), an iso-butyl group ( i Bu), tert-butyl group (tert-Bu, t Bu), sec-butyl group (sec-Bu, sec Bu), n-pentyl group ( n Pe), iso-pentyl group ( iso Pe), sec -pentyl group ( sec Pe), tert-pentyl group ( t Pe), neo- pentyl group ( neo Pe), 3-pentyl group, n-hexyl group, iso-hexyl group, heptyl group, 4,4-dimethylphen a tyl group, an octyl group, a 2,2,4-trimethylpentyl group
  • a first aspect of the present application provides a benzoselenophene-based compound, represented by the following Chemical Formula 1:
  • R 1 is a substituted or unsubstituted C 3-10 heterocycloalkyl group, a substituted or unsubstituted C 5-10 aryl group, or a substituted or unsubstituted C 3-10 heteroaryl group,
  • R 2 and R 3 are each independently hydrogen, fluorine, chlorine, bromine, iodine, or a substituted or unsubstituted C 1-5 alkyl group,
  • R 4 and R 5 are each independently hydrogen, or a substituted or unsubstituted C 1-5 alkyl group
  • the heterocycloalkyl group and the heteroaryl group include one or more heteroatoms selected from N, O, and S,
  • X is a halogen element
  • the substituents include an acyl group, an amino group (including simple amino groups, mono and dialkylamino groups, mono and diarylamino groups and alkylarylamino groups), an acylamino group ( carbamoyl group, and ureido group), alkylcarbonyloxy group, arylcarbonyloxy group, alkoxycarbonyloxy group, alkoxycarbonyl group, carboxy group, carboxylate group, aminocarbonyl group, mono and dialkylaminocarbonyl groups, Cyano group, azido group, halogen group, hydroxyl group, nitro group, trifluoromethyl group, thiol group, alkylthiol group, arylthiol group, alkylthiocarbonyl group, thiocarboxylate group, lower alkyl group, lower alkenyl group, lower Alkynyl group, cycloalkyl group, heterocycloalkyl group
  • R 1 is to include one or more nitrogen-containing, C 3-10 heterocycloalkyl group or C 3-10 heteroaryl group
  • R 4 and R 5 are, each independently, hydrogen, It may be a methyl group or an ethyl group, but may not be limited thereto.
  • X may be F, Cl, Br, or I, but may not be limited thereto. Also, in one embodiment of the present application, X may be Cl.
  • the benzoselenophene-based compound of the present application includes two sp 3 carbons as a main skeleton in -CHR 2 CHR 1 R 3 connected by an amide bond to the benzoselenophene parent, so that the flexibility of the molecule itself (flexibility) can be increased.
  • R 1 preferably includes various derivatives of a pentagonal or hexagonal ring including N, O, or S.
  • R 1 may include a double ring with or without a hetero atom, which may facilitate minor groove binding of DNA due to an anticancer mechanism.
  • R 1 is a pyrrolidinyl group (-NC 4 H 8 , pyrrolidinyl group), a piperidinyl group (-NC 5 H 10 , piperidinyl group), a piperazinyl group (-N 2 C 4 ) H 9 , piperazinyl group), 4-methylpiperazin -1-yl group (-N 2 C 5 H 11 , 4-methylpiperazin-1-yl group), morpholino group (-NOC 4 H 8 , morpholino group),
  • Y is to include -CH 2 - or -C 2 H 4 -
  • Z is to include -CHR-, -NR, -O-, or -S-, wherein R is It may include hydrogen or a C 1-3 alkyl group, but may not be limited thereto.
  • R 1 is a pyrrolidinyl group (-NC 4 H 8 , pyrrolidinyl group), a piperidinyl group (-NC 5 H 10 , piperidinyl group), a piperazinyl group (-N 2 C 4 ) H 9 , piperazinyl group), 4-methylpiperazin -1-yl group (-N 2 C 5 H 11 , 4-methylpiperazin-1-yl group), or morpholino group (-NOC 4 H 8 , morpholino group)yl can
  • R 2 and R 3 may be both hydrogen.
  • R 5 and R 6 may each independently be hydrogen, a methyl group, an ethyl group, or a propyl group.
  • the benzoselenophen-based compound may include:
  • a second aspect of the present application is to prepare an intermediate product by (a) reacting a carboxylic acid represented by the following formula (2) with an amine represented by the following formula (3); (b) reacting the intermediate product with an amine represented by the following formula (4) to obtain a benzoselenophene-based compound represented by the following formula (1).
  • R 1 is a substituted or unsubstituted C 3-10 heterocycloalkyl group, a substituted or unsubstituted C 5-10 aryl group, or a substituted or unsubstituted C 3-10 heteroaryl group,
  • R 2 and R 3 are each independently hydrogen, fluorine, chlorine, bromine, iodine, or a substituted or unsubstituted C 1-5 alkyl group,
  • R 4 and R 5 are each independently hydrogen or a substituted or unsubstituted C 1-5 alkyl group
  • R 6 is a substituted or unsubstituted C 1-5 alkyl group
  • the heterocycloalkyl group and the heteroaryl group include one or more heteroatoms selected from N, O, and S,
  • X is a halogen element
  • the substituents include an acyl group, an amino group (including simple amino groups, mono and dialkylamino groups, mono and diarylamino groups and alkylarylamino groups), an acylamino group ( carbamoyl group, and ureido group), alkylcarbonyloxy group, arylcarbonyloxy group, alkoxycarbonyloxy group, alkoxycarbonyl group, carboxy group, carboxylate group, aminocarbonyl group, mono and dialkylaminocarbonyl groups, Cyano group, azido group, halogen group, hydroxyl group, nitro group, trifluoromethyl group, thiol group, alkylthiol group, arylthiol group, alkylthiocarbonyl group, thiocarboxylate group, lower alkyl group, lower alkenyl group, lower Alkynyl group, cycloalkyl group, heterocycloalkyl group
  • R 1 is to include one or more nitrogen-containing, C 3-10 heterocycloalkyl group or C 3-10 heteroaryl group
  • R 4 and R 5 are, each independently, hydrogen, It may be a methyl group or an ethyl group, but may not be limited thereto.
  • X may be F, Cl, Br, or I, but may not be limited thereto. Also, in one embodiment of the present application, X may be Cl.
  • the benzoselenophene-based compound of the present application includes two sp 3 carbons as a main skeleton in -CHR 2 CHR 1 R 3 connected by an amide bond to the benzoselenophene parent, so that the flexibility of the molecule itself (flexibility) can be increased.
  • R 1 preferably includes a tertiary amine having a small substituent or various derivatives of a pentagonal or hexagonal ring including N, O, or S.
  • R 1 may include a double ring with or without a hetero atom, which may facilitate minor groove binding of DNA due to an anticancer mechanism.
  • R 1 is a pyrrolidinyl group (-NC 4 H 8 , pyrrolidinyl group), a piperidinyl group (-NC 5 H 10 , piperidinyl group), a piperazinyl group (-N 2 C 4 ) H 9 , piperazinyl group), 4-methylpiperazin -1-yl group (-N 2 C 5 H 11 , 4-methylpiperazin-1-yl group), morpholino group (-NOC 4 H 8 , morpholino group),
  • Y is to include -CH 2 - or -C 2 H 4 -
  • Z is to include -CHR-, -NR, -O-, or -S-, wherein R is It may include hydrogen or a C 1-3 alkyl group, but may not be limited thereto.
  • R 1 is a pyrrolidinyl group (-NC 4 H 8 , pyrrolidinyl group), a piperidinyl group (-NC 5 H 10 , piperidinyl group), a piperazinyl group (-N 2 C 4 ) H 9 , piperazinyl group), 4-methylpiperazin -1-yl group (-N 2 C 5 H 11 , 4-methylpiperazin-1-yl group), or morpholino group (-NOC 4 H 8 , morpholino group)yl can
  • R 2 and R 3 may be both hydrogen.
  • R 5 and R 6 may each independently be hydrogen, a methyl group, an ethyl group, or a propyl group.
  • the intermediate product produced in (a) may be in the form of a carboxylic acid or a carboxylate salt in which R 6 is substituted with hydrogen according to pH adjustment, but may not be limited thereto. .
  • the amine compound represented by Formula 4 may be one obtained by performing acid treatment on seco-MCBI represented as follows, which is known in the prior art, but may not be limited thereto:
  • the benzoselenophen-based compound may include:
  • a third aspect of the present application provides a pharmaceutical composition
  • a pharmaceutical composition comprising a benzoselenophen-based compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof, for preventing or treating a proliferative disease:
  • R 1 is a substituted or unsubstituted C 3-10 heterocycloalkyl group, a substituted or unsubstituted C 5-10 aryl group, or a substituted or unsubstituted C 3-10 heteroaryl group,
  • R 2 and R 3 are each independently hydrogen, fluorine, chlorine, bromine, iodine, or a substituted or unsubstituted C 1-5 alkyl group,
  • R 4 and R 5 are each independently hydrogen or a substituted or unsubstituted C 1-5 alkyl group
  • the heterocycloalkyl group and the heteroaryl group include one or more heteroatoms selected from N, O, and S,
  • X is a halogen element
  • the benzoselenophen-based compound or a pharmaceutically acceptable salt thereof may be a prodrug, but may not be limited thereto.
  • the benzoselenophen-based compound or a pharmaceutically acceptable salt thereof may form an active form when administered in a solvent or in the body, but may not be limited thereto.
  • the proliferative disease may include one or more selected from neoplasia, tumor, cancer, leukemia, psoriasis, bone disease, fibroproliferative disorder, and atherosclerosis, but is not limited thereto. may not be
  • the cancer is a solid tumor, blood cancer, colorectal cancer, uterine cancer, uterine fibroids, meningioma, lung cancer, small cell lung cancer, non-small cell lung cancer, gastrointestinal cancer, colorectal cancer, bowel cancer, breast cancer, ovarian cancer , prostate cancer, testicular cancer, liver cancer, kidney cancer, bladder cancer, pancreatic cancer, brain cancer, brain metastasis, sarcoma, osteosarcoma, Kaposi's sarcoma and melanoma, but may include one or more selected from melanoma, but may not be limited thereto.
  • the pharmaceutical composition according to one embodiment of the present application may be applicable to diseases that are not limited to carcinoma as a target for prevention or treatment.
  • the substituent is an acyl group, an amino group (including simple amino groups, mono and dialkylamino groups, mono and diarylamino groups and alkylarylamino groups), an acylamino group ( carbamoyl group, and ureido group), alkylcarbonyloxy group, arylcarbonyloxy group, alkoxycarbonyloxy group, alkoxycarbonyl group, carboxy group, carboxylate group, aminocarbonyl group, mono and dialkylaminocarbonyl groups, Cyano group, azido group, halogen group, hydroxyl group, nitro group, trifluoromethyl group, thiol group, alkylthiol group, arylthiol group, alkylthiocarbonyl group, thiocarboxylate group, lower alkyl group, lower alkenyl group, lower Alkynyl group, cycloalkyl group, heterocycloalkyl group,
  • R 1 is to include one or more nitrogen-containing, C 3-10 heterocycloalkyl group or C 3-10 heteroaryl group, wherein R 4 and R 5 are, each independently, hydrogen , a methyl group, or an ethyl group, but may not be limited thereto.
  • X may be F, Cl, Br, or I, but may not be limited thereto. Also, in one embodiment of the present application, X may be Cl.
  • the benzoselenophene-based compound of the present application includes two sp 3 carbons as a main skeleton in -CHR 2 CHR 1 R 3 connected by an amide bond to the benzoselenophene parent, so that the flexibility of the molecule itself (flexibility) can be increased.
  • R 1 preferably includes various derivatives of a pentagonal or hexagonal ring including N, O, or S.
  • R 1 may include a double ring with or without a hetero atom, which may facilitate minor groove binding of DNA due to an anticancer mechanism.
  • R 1 is a pyrrolidinyl group (-NC 4 H 8 , pyrrolidinyl group), a piperidinyl group (-NC 5 H 10 , piperidinyl group), a piperazinyl group (-N 2 C 4 ) H 9 , piperazinyl group), 4-methylpiperazin -1-yl group (-N 2 C 5 H 11 , 4-methylpiperazin-1-yl group), morpholino group (-NOC 4 H 8 , morpholino group),
  • Y is to include -CH 2 - or -C 2 H 4 -
  • Z is to include -CHR-, -NR, -O-, or -S-, wherein R is It may include hydrogen or a C 1-3 alkyl group, but may not be limited thereto.
  • R 1 is a pyrrolidinyl group (-NC 4 H 8 , pyrrolidinyl group), a piperidinyl group (-NC 5 H 10 , piperidinyl group), a piperazinyl group (-N 2 C 4 ) H 9 , piperazinyl group), 4-methylpiperazin -1-yl group (-N 2 C 5 H 11 , 4-methylpiperazin-1-yl group), or morpholino group (-NOC 4 H 8 , morpholino group)yl can
  • R 2 and R 3 may be both hydrogen.
  • R 5 and R 6 may each independently be hydrogen, a methyl group, an ethyl group, or a propyl group.
  • the benzoselenophen-based compound may include:
  • a fourth aspect of the present application is an antibody; linker; And it provides an antibody-drug conjugate (antibody-drug conjugate) or a pharmaceutically acceptable salt thereof, comprising a benzoselenophen-based compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof:
  • R 1 is a substituted or unsubstituted C 3-10 heterocycloalkyl group, a substituted or unsubstituted C 5-10 aryl group, or a substituted or unsubstituted C 3-10 heteroaryl group,
  • R 2 and R 3 are each independently hydrogen, fluorine, chlorine, bromine, iodine, or a substituted or unsubstituted C 1-5 alkyl group,
  • R 4 and R 5 are each independently hydrogen or a substituted or unsubstituted C 1-5 alkyl group
  • the heterocycloalkyl group and the heteroaryl group include one or more heteroatoms selected from N, O, and S,
  • X is a halogen element
  • the antibody-drug conjugate or a pharmaceutically acceptable salt thereof may be a prodrug, but may not be limited thereto.
  • the antibody-drug conjugate or a pharmaceutically acceptable salt thereof may form an active form when administered in a solvent or in the body, but may not be limited thereto.
  • the antibody may include, but may not be limited to, an antibody capable of immunospecifically acting against a proliferative disease, a modified antibody, or an antigen-binding fragment thereof.
  • the "antibody” is a concept that includes both a polyclonal antibody and a monoclonal antibody (monoclonal antibody, monoclonal antibody), and may preferably be a monoclonal antibody.
  • the whole antibody has a structure having two full-length light chains and two full-length heavy chains, and has a structure including a constant region, and each light chain is connected to the heavy chain by a disulfide bond.
  • the antibody is a monoclonal antibody, a multispecific antibody, a human antibody, a humanized antibody, a chimeric antibody, a single chain Fvs (scFV), a single chain antibody, a Fab fragment, an F (ab') fragment, disulfide-binding Fvs (sdFV) and anti-idiotypic (anti-Id) antibodies, or epitope-binding fragments of such antibodies, and the like.
  • scFV single chain Fvs
  • sdFV single chain antibody
  • Fab fragment an F (ab') fragment
  • disulfide-binding Fvs (sdFV) and anti-idiotypic (anti-Id) antibodies or epitope-binding fragments of such antibodies, and the like.
  • the whole antibody of the anti-c-Met antibody according to the embodiment of the present application is a concept including IgA, IgD, IgE, IgM and IgG forms, and IgG is a subtype, including IgG1, IgG2, IgG3 and IgG4.
  • the "modified antibody” herein includes a diabody, wherein the diabody refers to a single antibody having an antibody or antibody-binding fragment that recognizes different antigens, and the corresponding antibody is a cancer-associated antigen.
  • the "antigen-binding fragment” refers to a fragment having an antigen-binding function, and includes Fab, Fab', F(ab')2, scFv (scFv)2, scFv-Fc, and It is a concept including Fv and the like.
  • the proliferative disease may include one or more selected from neoplasia, tumor, cancer, leukemia, psoriasis, bone disease, fibroproliferative disorder, and atherosclerosis, but is not limited thereto. may not be
  • the proliferative disease may be particularly cancer, and the cancer is a solid tumor, hematologic cancer, colorectal cancer, uterine cancer, uterine fibroids, meningioma, lung cancer, small cell lung cancer, non-small cell lung cancer, gastrointestinal cancer , colorectal cancer, bowel cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer, liver cancer, kidney cancer, bladder cancer, pancreatic cancer, brain cancer, brain metastasis cancer, sarcoma, osteosarcoma, Kaposi's sarcoma and melanoma may be one comprising at least one selected from However, it may not be limited thereto.
  • the pharmaceutical composition according to one embodiment of the present application may be applicable to diseases that are not limited to carcinoma as a target for prevention or treatment.
  • the antibody may be an antibody that binds to one or more tumor-associated antigens or cell surface receptors selected from the following, but may not be limited thereto. In addition, it may bind to the following various antigens known in the prior art, but may not be limited thereto:
  • BMPR1B bone morphogenetic protein receptor-type 1B
  • E16 LAT1, SLC7A5
  • STEAP1 six transmembrane epithelial antigen of prostate
  • 0772P CA125, MUC16
  • MPF MPF, MSLN, SMR, megakaryocyte potentiating factor, mesothelin
  • Napi3b [NAPI-3B, NPTIIb, SLC34A2, solute carrier family 34 (sodium phosphate), member 2, type II sodium-dependent phosphate transporter 3b]
  • Sema 5b FLJ10372, KIAA1445, Mm.42015, SEMA5B, SEMAG, Semaphorin 5b H log, sema domain, seven thrombospondin repeats (type 1 and type 1-like), transmembrane domain (TM) and short cytoplasmic domain, (semaphorin) 5B
  • PSCA hlg (2700050
  • the antibody can be used without limitation as long as it is an antibody that can be used for the prevention and treatment of proliferative diseases, in particular, anticancer treatment, for example, alemtuzumab, apolizumab ), aselizumab, atlizumab, bapineuzumab, bevacizumab, bivatuzumab mertansine, cantuzumab mertansine, cedelizumab, certolizumab pegol, cetuximab, cidfusituzumab, cidtuzumab, daclizumab, eculizumab ), efalizumab, epratuzumab, erlizumab, ertumaxomab, felvizumab, fontolizumab, gemtuzumab, gemtuzumab Zumab ozogamicin, ibritumomab tiuxetan
  • anticancer treatment for
  • the linker is commonly used in the art and any linker useful for the antibody-drug conjugate may be used without limitation.
  • the linker is a chemical link that attaches the antibody and the drug, and maintains stability when circulated or distributed in the body, but is selectively cut only when it penetrates into the tumor and enters the cell to release the bound drug.
  • the linker is composed of an attachment-spacer-release, and a new linker can be developed by modifying and/or improving one or more components of an attachment, a spacer, and a release among commercially available linkers.
  • the linker may be used without limitation, not only the linkers commercially available in the art, but also newly developed linkers.
  • the linker may be conjugated to a drug by chemical conjugation or enzymatic conjugation, but may not be limited thereto.
  • the chemical conjugation may include lysine amide coupling, cysteine coupling, or non-natural amino acid incorporation by genetic engineering. , which may not be limited thereto.
  • the enzymatic conjugation is a peptide transfer using soltase (transpeptidation using sortase), a peptide transfer using a microbial transglutaminase (transpeptidation using microbial transglutaminase), or n-glycan engineering (n-glycan engineering) may include, but may not be limited thereto.
  • the linker may include one or more additional cleavable cleavable linkers or non-cleavable linkers, but may not be limited thereto.
  • the linker is a disulfide linker that is a reducible linker, an enzymatically cleavable linker, and a hydrazone linker that is a chemical-labile linker.
  • a protease-labile linker or a cleavable linker such as a glycosidase-sensitive linker
  • a non-cleavable bifunctional linker or a non-cleavable spacer linker (non-cleavable spacer linker) may include a non-cleavable linker such as, but is not limited thereto.
  • the linker may further comprise one or more additional cleavable linkers or non-cleavable linkers, preferably selected from the group consisting of: hydrazine linkers, thiourea linkers, self- Self-immolative linker, succinimidyl trans-4-(maleimidylmethyl)cyclohexane-1-carboxylate (SMCC) linker, disulfide linker , selenoether linkers, amide linkers, thioether linkers and/or maleimide linkers.
  • additional cleavable linkers or non-cleavable linkers preferably selected from the group consisting of: hydrazine linkers, thiourea linkers, self- Self-immolative linker, succinimidyl trans-4-(maleimidylmethyl)cyclohexane-1-carboxylate (SMCC) linker, disulfide linker , selenoether linkers, amide linkers, thioether linkers and/or
  • linkers may be suitable. These linkers are either non-cleavable or may be cleaved by pH changes, redox potentials or specific intracellular/extracellular enzymes. Cleavable oligopeptide linkers include protease- or matrix metalloprotease-cleavable linkers. It is understood that the linker may include any of the above combinations. For example, the linker may be a valine-citruline PAB linker.
  • the linker is a cleavable linker, N-succinimidyl-4-(2-pyridyldithio)pentanoate [N-succinimidyl-4-(2-pyridyldithio)pentanoate; SPP], N-succinimidyl-4-(2-pyridyldithio)butanoate [N-succinimidyl-4-(2-pyridyldithio)butanoate; SPDB], a disulfide linker such as sulfo-SPDB, MDS, DMDS, DSDM, or NDMDS; an enzymatically cleavable linker such as Phe-Lys-PABC, Val-Cit-PABC, Val-Ala-PABC, MHVCBC (valine-citrulline), or MHFKBC (phenylalanine-lysine); hydrazone linkers such as
  • the linker may include one selected from, but may not be limited thereto:
  • n is a number from about 1 to about 1,000.
  • n is about 1 to about 1,000, about 1 to about 900, about 1 to about 800, about 1 to about 700, about 1 to about 600, about 1 to about 500, about 1 to about 400, about 1 to about 300, about 1 to about 200, about 1 to about 100, about 1 to about 50, about 1 to about 40, about 1 to about 30, about 1 to about 20, about 1 to about 10 , may be a number from about 1 to about 5, from about 1 to about 3, but may not be limited thereto. In one embodiment of the present application, n may be a number from about 1 to about 5, or from about 1 to about 3.
  • the n number of polyethylene glycol (PEG) moieties of the linker for example, to have a molecular weight of about 1,000 or about 2,000, 4-arm, or 8-arm It may be used as an anticancer agent or a precursor thereof by synthesizing DNA alkylated derivatives containing a benzoselenophene-based compound having increased water solubility by forming branched PEG, but may not be limited thereto.
  • PEG polyethylene glycol
  • the antibody-drug conjugate of the present application may be a substance having a very strong anticancer effect as an IC 50 nM or pM unit for cancer cells, but may not be limited thereto.
  • the linker and the benzoselenophene-based compound may be linked by a peptide bond, but may not be limited thereto.
  • the substituent is an acyl group, an amino group (including simple amino groups, mono and dialkylamino groups, mono and diarylamino groups and alkylarylamino groups), an acylamino group ( carbamoyl group, and ureido group), alkylcarbonyloxy group, arylcarbonyloxy group, alkoxycarbonyloxy group, alkoxycarbonyl group, carboxy group, carboxylate group, aminocarbonyl group, mono and dialkylaminocarbonyl groups, Cyano group, azido group, halogen group, hydroxyl group, nitro group, trifluoromethyl group, thiol group, alkylthiol group, arylthiol group, alkylthiocarbonyl group, thiocarboxylate group, lower alkyl group, lower alkenyl group, lower Alkynyl group, cycloalkyl group, heterocycloalkyl group,
  • R 1 is to include one or more nitrogen-containing, C 3-10 heterocycloalkyl group or C 3-10 heteroaryl group
  • R 4 and R 5 are, each independently, hydrogen, It may be a methyl group or an ethyl group, but may not be limited thereto.
  • X may be F, Cl, Br, or I, but may not be limited thereto. Also, in one embodiment of the present application, X may be Cl.
  • the benzoselenophene-based compound of the present application includes two sp 3 carbons as a main skeleton in -CHR 2 CHR 1 R 3 connected by an amide bond to the benzoselenophene parent, so that the flexibility of the molecule itself (flexibility) can be increased.
  • R 1 preferably includes a tertiary amine having a small substituent or various derivatives of a pentagonal or hexagonal ring including N, O, or S.
  • R 1 may include a double ring with or without a hetero atom, which facilitates minor groove binding of DNA due to an anticancer mechanism.
  • R 1 is a pyrrolidinyl group (-NC 4 H 8 , pyrrolidinyl group), a piperidinyl group (-NC 5 H 10 , piperidinyl group), a piperazinyl group (-N 2 C 4 ) H 9 , piperazinyl group), 4-methylpiperazin -1-yl group (-N 2 C 5 H 11 , 4-methylpiperazin-1-yl group), morpholino group (-NOC 4 H 8 , morpholino group),
  • Y is to include -CH 2 - or -C 2 H 4 -
  • Z is to include -CHR-, -NR, -O-, or -S-, wherein R is It may include hydrogen or a C 1-3 alkyl group, but may not be limited thereto.
  • R 1 is a pyrrolidinyl group (-NC 4 H 8 , pyrrolidinyl group), a piperidinyl group (-NC 5 H 10 , piperidinyl group), a piperazinyl group (-N 2 C 4 ) H 9 , piperazinyl group), 4-methylpiperazin -1-yl group (-N 2 C 5 H 11 , 4-methylpiperazin-1-yl group), or morpholino group (-NOC 4 H 8 , morpholino group)yl can
  • R 2 and R 3 may be both hydrogen.
  • R 5 and R 6 may each independently be hydrogen, a methyl group, an ethyl group, or a propyl group.
  • the benzoselenophen-based compound may include:
  • the combination of the benzoselenophene-based compound of the present application and the linker may be prepared, for example, by the following method, but may not be limited thereto:
  • the drug-to-antibody ratio (DAR) in the antibody-drug conjugate may be in the range of about 1 to about 8, but may not be limited thereto. In one embodiment of the present application, the drug-antibody ratio (DAR) in the antibody-drug conjugate is about 1 to about 8, about 1 to about 6, about 1 to about 5, about 2 to about 8, about 2 to It may be about 6, about 2 to about 5, about 3 to about 8, about 3 to about 6, about 3 to about 5, but may not be limited thereto. Also, in one embodiment of the present application, the drug-antibody ratio (DAR) in the antibody-drug conjugate may be about 2 to about 5.
  • a fifth aspect of the present application provides an anticancer composition comprising the antibody-drug conjugate according to the fourth aspect or a pharmaceutically acceptable salt thereof.
  • the anticancer composition is a solid tumor, blood cancer, colorectal cancer, uterine cancer, uterine fibroids, meningioma, lung cancer, small cell lung cancer, non-small cell lung cancer, gastrointestinal cancer, colorectal cancer, colon cancer, breast cancer, It may have anticancer activity against at least one disease selected from ovarian cancer, prostate cancer, testicular cancer, liver cancer, kidney cancer, bladder cancer, pancreatic cancer, brain cancer, brain metastasis, sarcoma, osteosarcoma, Kaposi's sarcoma, and melanoma, but limited thereto it may not be
  • the pharmaceutical composition according to one embodiment of the present application may be applicable to diseases that are not limited to carcinoma as a target for prevention or treatment.
  • the MC layer was separated in a separatory funnel using MC (methylene chloride, methylene chloride)/water, dried over MgSO 4 and filtered. The filtered solution was removed from the solvent on a rotary evaporator and columned. Yield: 84%.
  • Seco-MCBI (Compound 1) used for the synthesis was synthesized using a known method.
  • the process of synthesizing compounds 3 and 4 by coupling benzoselenophene carboxylic acid to the intermediate obtained by acid treatment was performed as follows:
  • Dissolve compound 3 in anhydrous THF fill N 2 (g), add TEA (6 equivalents) and 4-nitrophenyl chloroformate (4-Nitrophenyl chloroformate, 4 equivalents) at 0° C., and react at room temperature for 12 hours. did it After evaporating all of the THF, phenol, pNPC, and TEA were removed by ether precipitation, and the next step was performed as crude.
  • the compound 3-1 was dissolved in TFA (20% under methylene chloride as a solvent) and the temperature was raised from 0° C. to room temperature. After confirming the reaction by HPLC, the reaction was repeated with MC, followed by the next reaction with crude. did.
  • the antibody was trastuzumab (TmAb) and was used after purification using a GPC column.
  • the antibody used has two disulfide bonds connecting HC-LC and two disulfide bonds connecting HC-HC, so there are a total of four interchain disulfide bonds. ) was used for partial reduction.
  • DAR trastuzumab
  • TCEP (2.75 equivalent) in an incubator for 30 minutes and then columned with GPC to obtain only the reduced antibody.
  • 1 mM DTPA was added.
  • mal-linker-drug 10 equivalents was dissolved in DMSO, and 2 equivalents were added. After checking with HIC every 30 minutes at 37°C in an incubator, add more.
  • each part of the reduced antibody is reduced (full reduction) and displayed separately on the spectrum, thereby confirming which part of the antibody is linked to the linker-drug.
  • FIG. 3 as a result of the reduction of the ADC, it was decomposed into a light chain and a heavy chain, not bound to the light chain (L0), one bound to the light chain (L1), and not bound to the heavy chain ( H0), and one, two, and three bonds to the heavy chain (H1, H2, and H3) were quantitatively analyzed. Accordingly, it was confirmed that the DAR was 4.25.
  • Compound 3 was checked for activity by requesting a sample to the NCI NPT program.
  • the GI 50 growth inhibition 50%, an index indicating activity in the NCI NPT program
  • CNS cancer, melanoma, and renal cancer show particularly strong activity.
  • Her2-expressing NCI-N87 is sensitive to Trastzumab-Compound 3 ADC, while Her2-negative MCF-7 is resistant.
  • trastuzumab-Glucuronide-Compound 3 ADC was treated with MCF-7 and NCI-N87, and intracellular ATP was measured to analyze the viability.
  • trastuzumab NCI-N87, which expressed the antigen showed high sensitivity
  • MCF7, which did not express the antigen showed low sensitivity.
  • ADC DS-24 potency and body weight change in NCI-N87 xenograft animal model
  • trastuzumab and trastuzumab-Glucuronide-Compound 2 [ADC (DS-24)] were administered intravenously, respectively, and then anticancer activity was observed. did.
  • trastuzumab was administered at 5 mg/kg twice a week, and ADC (DS-24) was administered once at a dose of 1 mg/kg and 5 mg/kg, respectively.
  • the trastuzumab administration group and the ADC (DS-24) 1 mg/kg administration group showed some degree of tumor formation inhibition, but there was no significance, and in the ADC (DS-24) 5 mg/kg administration group, the two It was confirmed that the size of the tumor did not increase significantly until day 49 compared to the branches.
  • the body weight of the mice did not change significantly during the administration period. Therefore, in the ADC (DS-24) administration group, side effects such as serious weight change were not found, and it was confirmed that toxicity did not appear.
  • the levels of inflammatory cells such as white blood cells (WBC), neutrocytes (NEU), lymphocytes (lymphocytes, LYM), and monocytes (MONO) in the control and administration groups were in the normal range.
  • WBC white blood cells
  • NEU neutrocytes
  • LYM lymphocytes
  • monocytes monocytes
  • anemia-related values such as red blood cells, hemoglobin, and hemoglobin showed no specific findings, and mean corpuscular volume (MCV), average red blood cell hemoglobin, etc. (mean corpuscular hemoglobin, MCH) and platelet count (PLT) were also confirmed.
  • 11A, 11B, and 11C are data confirming the cell viability inhibitory efficacy of compound 3 (DS-24) and 7 other payloads against the glioblastoma cell line U87MG, the multiple myeloma cell line KMS11, and the bladder cancer cell line RT112, respectively.
  • Fig. 12a, Fig. 12b, Fig. 12c, Fig. 12d, Fig. 12e, and Fig. 12f confirm the cell viability inhibitory effect of compound 3 (DS-24) and 7 types of payloads for 6 types of glioblastoma patient-derived cells, respectively. is data.
  • the analyzed IC 50 is shown in Table 2 below, and in the case of DM1, DM4, MMAE, and MMAF, the cell viability inhibitory effect on glioblastoma patient-derived cells was significantly reduced compared to KMS11 and RT112. SN-38 and Deruxtecan-linker showed similar efficacy in all cells, but it was confirmed that the cell viability inhibitory effect was lower than that of other payloads. DS-24 showed the highest cell viability inhibitory effect among the compared substances.
  • DS-24 exhibited an IC 50 that was about 100 to 1,000 times lower than that of other payloads compared in glioblastoma patient-derived cells and cell lines (U87MG). Therefore, it is considered that the DS-24 drug according to the present application inhibits cell viability very effectively compared to other drugs for brain tumor and glioblastoma.
  • the present inventors have previously prepared the following compound 2 and analyzed the anticancer activity, but it was confirmed that the following compound 3 according to the present invention has significantly superior anticancer activity than compound 2, specifically, with respect to the cell growth inhibitory effect A cell growth inhibition assay was performed:
  • Her-2 positive human gastric cancer cells NCI-N87 and human ovarian cancer cells SK-OV3 purchased from the American Type Culture Collection (ATCC; Manassas, VA, USA) were prepared in 384-well plates at 500 cells per well. (well plate) was seeded. After plating for 2 hours, cells were treated in quadruplicate with 5-fold toxin and 14-point serial dilution series. 5% CO 2 After incubation at 37° C. in a humidified incubator for 3 days, the cell viability was checked using an adenosine triphosphate monitoring system based on firefly luciferase (ATPliteTM 1step, PerkinElmer, MA, USA).
  • ATPliteTM 1step firefly luciferase
  • IC 50 values were calculated as average values of four repeated experiments (GraphPad Prism 5.0, CA, USA). Specific experimental values are shown in Table 3 below, and in FIGS. 13a and 13b, the cell viability according to the concentration of DS-24 and DS-26 for NCI-N87 was respectively shown, and in FIGS. 14a and 14b, SK- Cell viability according to the concentration of DS-24 and DS-26 for OV3 was shown, respectively:

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